Chemokine receptors comprise a large family of seven transmembrane domain G protein-coupled receptors differentially expressed in diverse cell types. Biological activities have been most clearly defined in leukocytes, where chemokines coordinate development, differentiation, anatomic distribution, trafficking, and effector functions and thereby regulate innate and adaptive immune responses. Pharmacological analysis of chemokine receptors is at an early stage of development. Disease indications have been established in human immunodeficiency virus/acquired immune deficiency syndrome and in Plasmodium vivax malaria, due to exploitation of CCR5 and Duffy, respectively, by the pathogen for cell entry. Additional indications are emerging among inflammatory and immunologically mediated diseases, but selection of targets in this area still remains somewhat speculative. Small molecule antagonists with nanomolar affinity have been reported for 7 of the 18 known chemokine receptors but have not yet been studied in clinical trials. Virally encoded chemokine receptors, as well as chemokine agonists and antagonists, and chemokine scavengers have been identified in medically important poxviruses and herpesviruses, again underscoring the importance of the chemokine system in microbial pathogenesis and possibly identifying specific strategies for modulating chemokine action therapeutically. The purpose of this review is to update current concepts of the biology and pharmacology of the chemokine system, to summarize key information about each chemokine receptor, and to describe a widely accepted receptor nomenclature system, ratified by the International Union of Pharmacology, that is facilitating clear communication in this area.

https://pharmrev.aspetjournals.org/content/pharmrev/52/1/145.full.pdf

International Union of Pharmacology. XXII. Nomenclature for Chemokine Receptors

Malaria is today a disease of poverty and underdeveloped countries In Africa, mortality remains high because there is limited access to treatment in the villages We should follow in Pasteur's footsteps by using basic research to develop better tools for the control and cure of malaria Insight into the complexity of malaria pathogenesis is vital for understanding the disease and will provide a major step towards controlling it Those of us who work on pathogenesis must widen our approach and think in terms of new tools such as vaccines to reduce disease The inability of many countries to fund expensive campaigns and antimalarial treatment requires these tools to be highly effective and affordable

The pathogenic basis of malaria

For decades, evolutionary biologists have argued that changes in cis-regulatory sequences constitute an important part of the genetic basis for adaptation. Although originally based on first principles, this claim is now empirically well supported: numerous studies have identified cis-regulatory mutations with functionally significant consequences for morphology, physiology and behaviour. The focus has now shifted to considering whether cis-regulatory and coding mutations make qualitatively different contributions to phenotypic evolution. Cases in which parallel mutations have produced parallel trait modifications in particular suggest that some phenotypic changes are more likely to result from cis-regulatory mutations than from coding mutations.

http://freethoughtblogs.com/pharyngula/files/2013/02/wray_evodevo.pdf

The evolutionary significance of cis -regulatory mutations

Recent studies have indicated that the attachment of bacteria to mucosal surfaces is the initial event in the pathogenesis of most infectious diseases due to bacteria in animals and humans. An understanding of the mechanisms of attachment and a definition of the adhesive molecules on the surfaces of bacteria (adhesins) as well as those on host cell membranes (receptors) have suggested new approaches to the prevention of serious bacterial infections: (1) application of purified adhesion or receptor materials or their analogues as competitive inhibitors of bacterial adherence; (2) administration of sublethal concentrations of antibiotics that suppress the formation and expression of bacterial adhesins; and (3) development of vaccines against bacterial surface components involved in adhesion to mucosal surfaces. Progress has already been made in the development of antiadhesive vaccines directed against the fimbrial adhesins of several human bacterial pathogens.

Bacterial Adherence: Adhesin-Receptor Interactions Mediating the Attachment of Bacteria to Mucosal Surfaces

Malarious patients experience asymptomatic parasitemia; acute febrile illness (with cerebral damage, anemia, respiratory distress, hypoglycemia); chronic debilitation (anemia, malnutrition, nervous system-related sequelae); and complications of pregnancy (anemia, low birth weight, increased infant mortality). These manifestations in patients, communities, and countries reflect intrinsic (human, parasite, mosquito) and extrinsic (environmental, social, behavioral, political, and economic conditions as well as disease-control efforts) determinants. At a minimum, between 700,000 and 2.7 million persons die yearly from malaria, over 75% of them African children. Between 400 and 900 million acute febrile episodes occur yearly in African children under 5 yr of age living in endemic areas. Although about half of these children are parasitemic, all merit consideration of malaria-specific therapy, which is becoming more problematic because of parasite resistance to drugs. These numbers will more than double over the next 20 yr without effective control. Fewer than 20% of these febrile episodes and deaths come to the attention of any formal health system. The relatively few ill patients who have any contact with the health services represent the "ears of the hippopotamus." Greatly intensified research activities and control of the intolerable burden of malaria are mandatory if economic development is to accelerate in Africa. In particular, support should be targeted to understanding and preventing malaria-induced anemia, hypoglycemia, effects on pregnancy, and neurologic and developmental impairment. To decrease and stop transmission of this intolerable scourge, there is an urgent need for malaria vaccines, newer drugs, and better vector control methods as well as the ability to improve current technologies and use them more efficiently.

The ears of the hippopotamus: manifestations, determinants, and estimates of the malaria burden.

Duffy-blood-group-negative human erythrocytes, FyFy, are resistant to invasion in vitro by Plasmodium knowlesi. The FyFy genotype is found predominantly in African and American blacks, who are the only groups completely resistant to infection by P. vivax. To determine if the FyFy genotype is the vivax resistance factor, we performed blood typing on 11 black and six white volunteers who had been exposed to the bites of P. vivax-infected mosquitoes. Only the five FyFy blacks were resistant to erythrocytic infection; the remaining six blacks and all whites had the Duffy-positive determinants (Fya or Fyb or both) and had contracted malaria. We conclude that Duffy determinants (Fya or Fyb or both) on the erythrocyte surface are required for invasion of erythrocytes by vivax merozoites.

The resistance factor to Plasmodium vivax in blacks. The Duffy-blood-group genotype, FyFy.

The interest in the article1 and letter2 on malaria in this week's Journal stems from developments in research into malarial sporozoites that may lead to an effective vaccine. Anopheline mosquitoes inject sporozoites into humans during a blood meal. Sporozoites rapidly disappear from the blood and enter liver parenchymal cells, where they proliferate during the next 7 to 10 days. Each sporozoite develops into thousands of parasites, each capable of invading an erythrocyte. This initiates the erythrocytic cycle, which causes disease and can lead to death. A vaccine that blocks the entry of sporozoites into liver cells will prevent disease. Immunity . . .

Louis H. Miller

Papers

The resistance factor to Plasmodium vivax in blacks. The Duffy-blood-group genotype, FyFy.

Research in Malaria Vaccines